Methods for inhibiting CGRP binding

Abstract

This invention relates to antagonists of calcitonin gene related peptide and in particular the invention relates to amino terminal modifications to peptides to improve their ability to bind to a member of the CGRP-receptor superfamily.

What is claimed is:  
     
       1. A method for inhibiting CGRP binding to one or more CGRP receptors comprising contacting a CGRP receptor with a composition comprising a peptide having the general formula: 
       
         
           R 1 —X—Z  
         
       
       wherein Z is a CGRP receptor-binding peptide, R 1  is an organic group, X is                    
       and wherein R 2  and R 3  are independently H or an organic group and n is a whole integer between 1 and 10;  
       in an amount effective to inhibit CGRP binding to one or more CGRP receptors.  
     
     
       2. The method of  claim 1  wherein the CGRP receptor is on a cell. 
     
     
       3. The method of  claim 2  wherein the cell is in culture. 
     
     
       4. The method of  claim 2  wherein the cell is part of a tissue. 
     
     
       5. The method of  claim 2  wherein the cell is in an animal. 
     
     
       6. The method of  claim 5  wherein the animal is a human. 
     
     
       7. The method of  claim 1  wherein the CGRP receptor is cell free. 
     
     
       8. The method of  claim 1  wherein Z is a peptide fragment of at least 15 amino acids from CGRP. 
     
     
       9. The method of  claim 8  wherein Z comprises the amino acid sequence of SEQ ID NO:1 or SEQ ID NO:2. 
     
     
       10. The method of  claim 1  wherein Z is an antagonist of human CGRP. 
     
     
       11. The method of  claim 1  wherein Z is an antagonist of α-CGRP or β-CGRP. 
     
     
       12. The method of  claim 11  wherein Z comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:6-17 and 23. 
     
     
       13. The method of  claim 11  wherein Z comprises an amino acid sequence selected from the group consisting of SEQ ID NOS:18-22. 
     
     
       14. The method of  claim 1  wherein Z is a CGRP antagonist peptide fragment selected from the group consisting of amylin, CGRP and adrenomedullin. 
     
     
       15. The method of  claim 1  wherein R 1  is an aromatic group, a heterocyclic group or an alkyl group and R 2  and R 3  are independently H, an aromatic group or an alkyl group. 
     
     
       16. The method of  claim 15  wherein R 1  is a C1-C4 alkyl group. 
     
     
       17. The method of  claim 16  wherein R 1  is a fluoroalkyl. 
     
     
       18. The method of  claim 16  wherein R 2  and R 3  are independently H, a C1-C4 alkyl group or a phenyl moiety. 
     
     
       19. The method of  claim 16  wherein R 1  is a C5-C10 aromatic group, a C5-C9 heterocyclic group or a C1-C4 alkyl group. 
     
     
       20. The method of  claim 19  wherein R 2  and R 3  are independently H or a C5-C10 aromatic group or a C1-C4 alkyl group. 
     
     
       21. The method of  claim 15  wherein R 1  has the general formula:                    
       and wherein R 4 -R 8  are each independently selected from the group of H, fluoro, chloro, bromo, iodo, nitro, nitrile (cyano), amino, N-methyl amino, N,N-dimethyl amino, hydroxy, methoxy, thiomethoxy (S-methyl), methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, trifluoromethoxy, vinyl, acetamido, phenyl, toluyl, and methoxyphenyl.  
     
     
       22. The method of  claim 21  wherein R 6  is trifluoromethyl and R 4 , R 5 , R 7  and R 8  are F. 
     
     
       23. The method of  claim 21  wherein the peptide is a CGRP antagonist having at least 15 consecutive amino acids selected from a protein from the group consisting of N-α-benzoyl-α-CGRP, N-α-benzyl-β-CGRP, N-αbenzoyl-β-CGRP and N-α-benzyl-α CGRP, dibenzyl-h-α-CGRP and dibenzyl-h-β-CGRP. 
     
     
       24. The method of  claim 15  wherein R 1  is                    
       and wherein Y is selected from the group consisting of O, NH, and S.  
     
     
       25. The method of  claim 15  wherein R 1  is selected from the group consisting of:                    
       and wherein X is selected from the group consisting of C and N.  
     
     
       26. The method of  claim 1  wherein Z is a vasoactive peptide. 
     
     
       27. The method of  claim 26  wherein Z is an antagonist of human CGRP.